Intrauterine growth-restriction (IUGR) due to stress causes fetal metabolic dysfunction in late gestation, which persists after birth and worsens as the individual ages. Our long-term goal is to identify molecular mechanisms that can be modified with maternally-delivered bioactive compounds to improve glucose homeostasis and metabolic function in the IUGR fetus. We have observed impaired glucose-stimulated insulin secretion and muscle glucose oxidation in IUGR fetal and neonatal sheep. We also recently identified enhanced TNFR1 and TLR4 pathways in IUGR fetal tissues, which we hypothesize are underlying mechanisms that disrupt glucose oxidation, insulin secretion, and metabolic homeostasis. Thus, the overarching objective for this study is to determine the extent to which mitigating the heightened activity of TNFR1 and TLR4 pathways improves these deficits. The study will be performed using the hyperthermic pregnant ewe model, which is a well-established biomedical model that mimics the human IUGR phenotype. TNFR1 and TLR4 activity will be moderated by infusing catheterized IUGR fetuses daily with eicosapentaenoic acid and docosahexaenoic acid, as these ?-3 fatty acids are known to reduce the activity of both pathways. In Specific Aim 1, we will perform in vivo and ex vivo studies to measure fetal whole-body and muscle-centric glucose metabolism. This will allow us to determine the role that heightened TNFR1 and TLR4 activity plays in the glucose metabolism deficits previously observed in the IUGR fetus. In Specific Aim 2, we will assess fetal glucose-stimulated insulin secretion and islet morphology to determine the role of heightened TNFR1 and TLR4 activity in ? cell dysfunction and impaired islet development. In addition, we will measure indicators of fat homeostasis and assess the total transcriptomes of fetal muscle and islet tissues. This will provide a more comprehensive understanding of the wider mechanistic changes that occur in these tissues in response to intrauterine stress, including additional regulatory pathways that may be involved in the IUGR metabolic phenotype. Currently, there are no treatment options for improving metabolic health status in IUGR-born children and adults due to the gap in our understanding of the underlying adaptive mechanisms. However, the findings of this study are expected to reveal that heightened TNFR1 and TLR4 activity has a key role in impaired muscle glucose oxidation and ? cell dysfunction and thus are appropriate mechanistic targets to moderate metabolic programming effects. This would fill a need by establishing the basis for prenatal prevention of the metabolic dysfunction that places IUGR-born babies at greater risk for metabolic disorders.